EP4039258A1 - Utilisation de diazépam en tant qu'agoniste du récepteur de benzodiazépine seulement toléré chez des patients atteints de la covid-19 - Google Patents

Utilisation de diazépam en tant qu'agoniste du récepteur de benzodiazépine seulement toléré chez des patients atteints de la covid-19 Download PDF

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EP4039258A1
EP4039258A1 EP21305168.3A EP21305168A EP4039258A1 EP 4039258 A1 EP4039258 A1 EP 4039258A1 EP 21305168 A EP21305168 A EP 21305168A EP 4039258 A1 EP4039258 A1 EP 4039258A1
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Prior art keywords
cov
sars
diazepam
bzra
patients
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EP21305168.3A
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German (de)
English (en)
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Nicolas HOERTEL
Frédéric LIMOSIN
Marina Lucia SANCHEZ RICO
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Assistance Publique Hopitaux de Paris APHP
Universite de Paris
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Assistance Publique Hopitaux de Paris APHP
Universite de Paris
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Priority to EP21305168.3A priority Critical patent/EP4039258A1/fr
Priority to PCT/EP2022/053013 priority patent/WO2022167685A1/fr
Publication of EP4039258A1 publication Critical patent/EP4039258A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention is based on the finding that Benzodiazepine Receptor Agonists (BZRA), including benzodiazepines and Z-drugs, are significantly associated with increased mortality among patients hospitalized for COVID-19, with a significant dose-dependent relationship. It is therefore suggested to decrease the dose or to taper off these medications, when possible, in these patients. Importantly, this lethal association was not observed for only one BZRA, namely diazepam. This knowledge will help guide clinicians on the choice of the molecule to prescribe to patients with COVID-19 with clinical indication of a BZRA treatment (e.g. patients with benzodiazepine use disorder, delirium tremens, epilepsy, alcohol withdrawal symptoms, etc).
  • BZRA Benzodiazepine Receptor Agonists
  • SARS-CoV-2 belongs to the species Coronavirus , in the genus Betacoronavirus and family Coronaviridae.
  • Coronaviruses are enveloped viruses with a helically symmetrical capsid. They have a single-stranded, positive-sense RNA genome and are capable of infecting cells in birds and mammals.
  • the morphology of the virions is typical, with a halo of protein protuberances ('Spike') which gave them their name of 'crown virus'.
  • Betacoronavirus genus comprising virus infecting animals and/or humans, is subdivided into four lineages designated as A, B, C and D:
  • Betacoronaviruses of the greatest clinical importance concerning humans are:
  • coronavirus infections can cause respiratory pathologies associated with symptoms similar to the common cold, bronchiolitis and more serious diseases such as the Severe Acute Respiratory Syndrome caused by SARS-CoV-1, which generated an epidemic in 2003, and the Middle Eastern Respiratory Syndrome caused by MERS-CoV, which generated an epidemic in 2012.
  • SARS-CoV-2 is the betacoronavirus causing the coronavirus epidemic of 2019-2021, generating the form of pneumonia known as coronavirus disease 2019 or COVID-19.
  • Symptoms of infection with SARS-CoV-2 are roughly similar to those of seasonal influenza infections: they include fever, fatigue, dry cough, shortness of breath, difficult breathing, pneumonia, renal failure, and may lead to death in severe cases.
  • BZRAs Benzodiazepine receptor agonists
  • GABA neurotransmitter gamma-aminobutyric acid
  • BZRAs This association between BZRAs and mortality might be explained by several mechanisms.
  • BZRA use may favor the occurrence of this condition 41 which is associated with unfavorable COVID-19 disease prognosis 43 .
  • BZRAs are known not only as efficient muscle relaxants and sedatives, but also effective for treating epilepsy, alcohol withdrawal syndrome, and acute behavioural disturbance 5 . All these disorders are highly problematic in the handling of COVID patients, as COVID severe to most aggressive forms require a stay in intensive care unit (ICU) and therefore a quiet behavior for a long time. Alternative yet as efficient medications are therefore need to replace BZRAs in these applications.
  • ICU intensive care unit
  • diazepam is not associated with increased mortality contrary to other BZRAs could be explained by several preclinical findings.
  • a prior study suggests 44 that the acid sphingomyelinase (ASM) / ceramide system may play a role in SARS-CoV-2 infections and that the formation of ceramide-enriched membrane platforms may mediate the entry of the virus into epithelial cells.
  • ASM acid sphingomyelinase
  • ceramide-enriched membrane platforms may mediate the entry of the virus into epithelial cells.
  • diazepam has been shown to interact with the acyl coenzyme A binding protein, also known as 'diazepam binding inhibitor', a protein that contributes to ceramide synthesis 45 . This interaction may result in a reduced ceramide synthase and, finally, reduced cellular ceramide concentration.
  • Rhinovirus activates the ASM, induces ceramide and the formation of ceramide-enriched membrane domains, which serve as entrance for the virus.
  • Other viruses require the ASM/ceramide system for endosomal escape 55 .
  • the ASM/ceramide mechanism also applies to non-viral infections such as Pseudomonas aeruginosa 47 , Staphylococcus aureus 52 and Neisseriae gonorrhoeae 53;54 .
  • the present inventors hereby propose to use Diazepam in patients suffering from a viral or bacterial infection, if and when they require any BZRA (i.e., either as a new treatment or as a switch instead of another BZRA, if this treatment is indicated).
  • Said viral infection can be due for example to the SARS-COV-2 virus, to a Rhinovirus, the Ebola virus, the measles virus or the Japanese encephalitis virus.
  • Said bacterial infection can be due to the bacteria Pseudomonas aeruginosa, Staphylococcus aureus or Neisseriae gonorrhoeae.
  • Betacoronavirus designates any virus belonging to the Betacoronavirus genus ( ⁇ -CoVs or Beta-CoVs), in particular any betacoronavirus belonging to one of the four lineages designated as A, B, C and D. It designates a betacoronavirus infecting animals and/or humans. In particular, this designation includes the betacoronaviruses infecting human organisms chosen among OC43, HKU1, SARS-CoV-1, SARS-CoV-2 and MERS-CoV.
  • viral infection due to at least one betacoronavirus designates the fact that host cells of an organism have been infected by at least one betacoronavirus, the whole organism being said to have a viral infection.
  • a betacoronavirus infection in humans is usually diagnosed by a healthcare professional, based on observation of the infected patient's symptoms. Additional biological tests may be required to confirm the diagnosis: blood and/or sputum and/or bronchoalveolar fluid tests.
  • Infection by a betacoronavirus can be established, for example, by molecular biological detection and/or viral titration of respiratory specimens, or by assaying blood for antibodies specific for said betacoronavirus.
  • Conventional diagnostic methods comprise techniques of molecular biology such as PCR, which is well known to the person in the field.
  • COVID-19 disease mean the disease linked to the infection with the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2).
  • a "symptomatic COVID-19 disease” is characterized by a patient who shows at least one symptom of the COVID-19 disease.
  • the most common symptoms of the COVID-19 disease are fever, muscle aches, headaches, fatigue, loss of taste and smell and respiratory symptoms such as a dry cough, difficulty breathing and a lack of oxygen.
  • a symptomatic disease is in contrast to an asymptomatic disease which is characterized by a patient who is a carrier for a disease or infection but experiences no symptoms.
  • betacoronavirus disease such as COVID-19
  • the following forms are usually observed:
  • the "severe symptomatic COVID-19 disease” is characterized by severe symptoms of the COVID-19 disease, in particular respiratory symptoms. Severe symptoms are acute respiratory distress syndrome that requires hospitalization of the patient in any unit, and especially in the intensive care unit (ICU) in case of critical infection.
  • ICU intensive care unit
  • COVID-19 patients are human patients infected with the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), whatever the form of the disease is.
  • SARS-COV-2 serum-derived neurotrophic factor-2
  • these patients are also herein called “SARS-COV-2" positive subjects, because they have received a positive result with at least one of this conventional diagnostic method (e.g., PCR test or serologic test or an antigenic test).
  • this conventional diagnostic method e.g., PCR test or serologic test or an antigenic test.
  • the methods of the invention can be also advantageously applied to any subject that is not yet infected by the SARS-COV-2 virus, but may have been exposed to said virus (close contact), or is likely to be exposed to the SARS-COV-2 virus in his / her daily routine (e.g., medical doctors, medical assistants, nurses, nursing assistants, home health aides, physicians, therapists, pharmacists, diagnostic medical sonographers, clinical laboratory technicians, dentists, dental assistants, emergency medical technicians, radiologic technologists, physical therapists, dental hygienists, respiratory therapists, anesthesiologists, obstetrician, surgeons, etc.). These subjects are herein called "SARS-COV-2 exposed”.
  • SARS-COV-2 exposed e.g., medical doctors, medical assistants, nurses, nursing assistants, home health aides, physicians, therapists, pharmacists, diagnostic medical sonographers, clinical laboratory technicians, dentists, dental assistants, emergency medical technicians, radiologic technologists, physical therapists, dental
  • SARS-COV-2 exposed subjects are subjects that have been in unprotected close contact with at least one SARS-COV-2 positive subject.
  • unprotected close contact it is herein meant that the subject has been exposed to the SARS-COV-2 virus, by being in contact with a SARS-COV-2 positive subject without carrying (or protected by) an effective protection at less than two meters, preferably less than one meter, whatever the duration of the contact was.
  • Said effective protection can be a surgical mask, a FFP2 mask, a cloth mask or an hygiaphone or any other effective protection.
  • the methods and use of the invention may be applied to "SARS-COV-2 negative" subjects.
  • the subjects should be “SARS-COV-2 negative” at least when the BZRA treatment (Diazepam or another BZRA) is administered.
  • SARS-COV-2 negative it is herein meant that the subject has received a negative result with at least one of the conventional diagnostic assay (e.g., PCR test or serologic test or an antigenic test), said assay being done no more than one day, preferably no more than few hours, before the BZRA treatment is administered.
  • the conventional diagnostic assay e.g., PCR test or serologic test or an antigenic test
  • SARS-COV-2 negative subjects are more preferably individuals that have been efficiently immunized against the SARS-COV-2 virus, by natural immunization (earlier infection) or by vaccinal immunization. Even more preferably, they can also be inhabitants that live in a country where no SARS-COV-2 infection is expected (e.g., an island where SARS-COV-2 is not present).
  • these "SARS-COV-2 negative subjects" have been negatively tested for a SARS-COV-2 infection by molecular biological detection and/or viral titration of respiratory specimens, or by assaying blood for antibodies specific for said betacoronavirus.
  • said subject is a human patient.
  • Said patient can be older than 75 years old, between 65 and 74 years old, between 18 and 65 years old, or below 18 years old.
  • said human patient is older than 50 years old, even more preferably older than 70 years old.
  • BZRA encompasses drugs having a benzodiazepine chemical structure, as well as z-drugs.
  • BZRA also called “BZRA drugs” or “BZRA compounds” or “BZRA agents”
  • BZRA drugs also called “BZRA drugs” or “BZRA compounds” or “BZRA agents”
  • BZRA agents can be for example chosen in the group consisting of:
  • These drugs have regulatory approval for the management of anxiety and panic disorders, and short-term treatment of insomnia, seizures, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal, sedation, and spasticity. They are also often used in an off-label manner to treat conditions such as anxious depression or the behavioral and psychological symptoms of dementia, which are also referred to as responsive behavior.
  • the subject to be treated may suffer from anxiety, panic disorders, insomnia, seizures, sedation, depression, acute behavioral disturbance, delirium, dementia and/or spasticity. Also, he/she may suffer from alcohol withdrawal, benzodiazepine withdrawal, or opiate withdrawal.
  • the present invention is thus drawn to any of these BZRA for use in the prevention and/or treatment of anxiety, panic disorders, insomnia, seizures, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal, sedation, depression, acute behavioral disturbance, dementia and/or spasticity, wherein said BZRA is used only in SARS-COV-2 negative subjects.
  • the present invention relates to the use of any BZRA (including Diazepam), to prepare a medicament intended to treat patients suffering from anxiety, panic disorders, insomnia, seizures, alcohol withdrawal, benzodiazepine withdrawal, opiate withdrawal, sedation, depression, acute behavioral disturbance, delirium, dementia and/or spasticity, as long as they are not infected with the virus SARS-COV-2.
  • the present invention also discloses a method for preventing and/or treating anxiety, panic disorders, insomnia, seizures, alcohol withdrawal, benzodiazepine withdrawal, opiate withdrawal, sedation, depression, acute behavioral disturbance, delirium, dementia and/or spasticity in a subject, said method comprising administering to said subject an effective amount of any BZRA, only if he/she has not been diagnosed to be infected with the virus SARS-COV-2.
  • the method of the invention can comprise a diagnosis step as preliminary step.
  • said method may comprise the following steps:
  • the treated subjects are preferably "SARS-COV-2 negative" when said BZRA treatment is administered.
  • SARS-COV-2 negative when said BZRA treatment is administered.
  • the conventional diagnostic method e.g., PCR test or serologic test or an antigenic test
  • they have been efficiently immunized against the SARS-COV-2 virus by a COVID vaccine or by an earlier infection, or they live in a country where no SARS-COV-2 infection is present or expected (e.g., an island where said virus has not been detected or has been eradicated).
  • administering BZRAs remains recommended for treating anxiety, panic disorders, insomnia, seizures, alcohol withdrawal, benzodiazepine withdrawal, opiate withdrawal, sedation, depression, acute behavioral disturbance, delirium, dementia and/or spasticity in SARS-COV-2 immunized subject.
  • the present inventors hereby recommend not to use BZRAs in patients suffering from a viral or bacterial infection, said infection being due to a Rhinovirus, the Ebola virus, the measles virus or the Japanese encephalitis virus or to the bacteria Pseudomonas aeruginosa, Staphylococcus aureus or Neisseriae gonorrhoeae.
  • the present invention is drawn to an in vitro method for preventing severe forms of COVID 19 disease to occur in a patient treated by a BZRA drug, said method comprising deprescribing said BZRA drug in said patient.
  • the present invention more precisely concerns a method for preventing severe forms of COVID19 disease to occur in a patient treated by a BZRA drug, said method comprising the steps of :
  • step b) is to be applied as soon as said subject receives a positive result with at least one of this conventional diagnostic method (e.g., PCR test or serologic test or an antigenic test).
  • this conventional diagnostic method e.g., PCR test or serologic test or an antigenic test.
  • Diazepam if the patient was already treated with Diazepam, then there is no need to change the treatment. In some cases, it may be recommended to decrease the Diazepam dose, if possible, because this treatment (as well as all BZRAs) are only indicated for short-term use.
  • administering diazepam instead of other BZRAs in subjects that are under treatment with BZRAs will help impairing anxiety, seizures, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, trouble sleeping, acute behavioral disturbance, dementia, delirium, restless legs syndrome, epilepsy, or will help inducing sedation before an invasive chirurgical operation in said subjects, and will prevent severe form of the COVID19 disease to develop, and possibly death to occur, if and once the subject gets infected with the SARS COV-2 virus.
  • a better prognosis could be acknowledged, as compared to COVID patients still receiving their current dose of BZRA.
  • the present invention concerns a method for treating agitation, anxiety, panic, muscle spasms, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal, trouble sleeping, dementia, delirium, acute behavioral disturbance, restless legs syndrome, or for preventing epileptic seizure and/or treating epilepsy, or for inducing pre-or post-operative sedation, anxiolysis, or amnesia in a subject in need thereof, said method comprising the steps of:
  • Step b) or c) is to be applied as soon as said subject receives a positive result with at least one of this conventional diagnostic method (e.g., PCR test or serologic test or an antigenic test).
  • this conventional diagnostic method e.g., PCR test or serologic test or an antigenic test.
  • Step b) or c) is to be applied as soon as said subject receives a positive result with at least one of this conventional diagnostic method (e.g., PCR test or serologic test or an antigenic test).
  • this conventional diagnostic method e.g., PCR test or serologic test or an antigenic test.
  • the present invention concerns a method for treating agitation, anxiety, panic, muscle spasms, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal, trouble sleeping, acute behavioral disturbance, dementia, delirium, restless legs syndrome or for preventing epileptic seizure and/or treating epilepsy, or for inducing pre-or post-operative sedation, anxiolysis, or amnesia in a subject in need thereof in a subject in need thereof, said method comprising the steps of :
  • BZRA drugs act as allosteric modulators of gamma-aminobutyric acid (GABA) activity by binding to inotropic benzodiazepine receptors at the GABA A receptor complex. They increase GABA binding and chloride ion channel opening, facilitating their inhibitory activity.
  • GABA gamma-aminobutyric acid
  • Some of these drugs have a benzodiazepine chemical structure (e.g., alprazolam, bromazepam, chlordiazepoxide, cobazam, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam), while others do not and are referred to as "non-benzodiazepine receptor agonists", “novel benzodiazepine receptor agonists", or "z-drugs” (e.g., zolpidem, zopiclone).
  • a benzodiazepine chemical structure e.g., alprazolam, bromazepam, chlordiazepoxide, cobazam, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, mid
  • BZRA encompass drugs having a benzodiazepine chemical structure as well as z-drugs.
  • BZRA drugs are therefore chosen in the group consisting of:
  • the patient may suffer from anxiety, panic disorders, insomnia, seizures, alcohol withdrawal, sedation, depression, acute behavioral disturbance, dementia, delirium, and/or spasticity, for which a BZRA was initially prescribed by a physician. Also, he/she may suffer from alcohol withdrawal, benzodiazepine withdrawal, or opiate withdrawal for which a BZRA was initially prescribed by a physician.
  • the present inventors hereby recommend to deprescribe BZRAs in patients suffering from a viral or bacterial infection, said infection being due to a Rhinovirus, the Ebola virus, the measles virus or the Japanese encephalitis virus or to the bacteria Pseudomonas aeruginosa, Staphylococcus aureus or Neisseriae gonorrhoeae.
  • Diazepam has to be preferred to other benzodiazepines among patients with COVID-19 requiring this treatment.
  • the present invention relates to the Diazepam treatment of patients that have been infected by - or are exposed to - the SARS-COV-2 virus and experience (or may experience) agitation, anxiety, panic, muscle spasms, trouble sleeping, and restless legs syndrome.
  • these patients were not previously treated with any BZRA.
  • this treatment can also benefit to patients that are at risk of delirium (due to old age or dementia or to multiple comorbidities), or those who are epileptic.
  • administration of Diazepam which is an anticonvulsant, will indeed prevent epileptic seizure to occur, for example if and once the patient is admitted in the Intensive Care Unit.
  • this treatment should solely involve Diazepam and no other BZRA.
  • the present invention relates to Diazepam for use in preventing severe forms of COVID19 disease to occur in SARS-COV-2 positive subjects or SARS-COV-2 exposed subjects that are treated with a Benzodiazepine Receptor Agonist (BZRA) other than Diazepam.
  • BZRA Benzodiazepine Receptor Agonist
  • Diazepam is administered for its authorized or classical therapeutic indications, namely:
  • the present invention relates to the use of Diazepam, to prepare a medicament intended to prevent severe forms of the COVID19 disease to occur in patients that have been diagnosed to be infected with the virus SARS-COV-2 (SARS-COV-2 positive subjects) or that have been exposed to the virus SARS-COV-2, should they suffer from agitation, anxiety, panic, muscle spasms, trouble sleeping, delirium, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal, acute behavioral disturbance, dementia and restless legs syndrome, or from epilepsy, or should they have to undergo an operation.
  • the present invention also relates to Diazepam, for use in preventing and/or treating agitation, anxiety, panic, muscle spasms, trouble sleeping, delirium, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal, acute behavioral disturbance, dementia, and restless legs syndrome in patients suffering from COVID19 (SARS-COV-2 positive subjects) or likely to suffer from the COVID19 (i.e., in SARS-COV-2 exposed subjects).
  • the present invention also relates to Diazepam, for use in preventing epileptic seizure and/or treating epileptic patients suffering from COVID19 (SARS-COV-2 positive subjects) or likely to suffer from the COVID19 (i.e., in SARS-COV-2 exposed subjects).
  • Diazepam is a well-known medicine marketed under several names: Valium ® , Valrelease ® , Vazepam ® , Diaz Intensol ® , Diastat ® , Dizac ® . Its chemical structure is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. As all 1,4-benzodiazepine, it binds with high affinity to the GABA A receptor in the brain to reduce arousal and to affect emotions. Diazepam's action causes an increase in affinity of the major inhibitory neurotransmitter, GABA. GABA binds mainly to the A subunit while Diazepam binds to the B subunit.
  • Diazepam increases chloride transport through ion-channels and ultimately reduces the arousal of the cortical and limbic systems in the CNS. Diazepam depresses the electrical after-discharge in the amygdala and hippocampus regions of the limbic system that affect emotions.
  • Diazepam is preferably administered by systemic oral administration. Intravenous or intramuscular injection is also possible after preparing a solution from crushed tablets. Commercially available liquid Valium ® can be injected, and gel forms can be rectally administered.
  • Diazepam is intended to treat patients suffering from an asymptomatic or symptomatic COVID-19 disease, and advantageously from a strong or severe symptomatic COVID-19 disease, as defined above.
  • Diazepam is administered to SARS-COV-2 positive subjects that experience for example difficulty in breathing and/or a lack of oxygen, to prevent agitation, anxiety, panic, muscle spasms, trouble sleeping, epileptic seizure, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal acute behavioral disturbance, dementia, delirium, and restless legs syndrome in same.
  • Diazepam will prevent a severe form of the COVID19 disease to develop, and will lower the risk of unvoluntary seizures or agitated states that may complicate the intubation protocols and therefore facilitate the treatment of the patients so as, eventually, to increase their survival rate.
  • the present inventors hereby recommend to use Diazepam to prevent agitation, anxiety, panic, muscle spasms, trouble sleeping, epileptic seizure, benzodiazepine withdrawal, opiate withdrawal, alcohol withdrawal acute behavioral disturbance, dementia, delirium, and restless legs syndrome in patients suffering from a viral or bacterial infection, said infection being due to a Rhinovirus, the Ebola virus, the measles virus or the Japanese encephalitis virus or to the bacteria Pseudomonas aeruginosa, Staphylococcus aureus or Neisseriae gonorrhoeae. All the above detailed embodiments can also be applied to any of these viral or bacterial - infected subjects, to prevent strong / severe forms of the infections and subsequent lethality to occur.
  • the present invention relates to the treatment of patients that have been infected by SARS-COV-2 (SARS-COV-2 positive subjects) or that have been exposed to SARS-COV-2 and that have to undergo a harmful or invasive medical procedure (e.g., operation or endoscopy).
  • SARS-COV-2 SARS-COV-2 positive subjects
  • SARS-COV-2 SARS-COV-2 positive subjects
  • a harmful or invasive medical procedure e.g., operation or endoscopy.
  • Diazepam will therefore advantageously induce sedation, anxiolysis or amnesia, before or after said medical procedure is performed, without worsening the outcome of the COVID disease, if the patient becomes infected. Also, it will prevent the worsening of the COVID 19 disease, if the patient is infected or likely to be infected.
  • the present invention is drawn to Diazepam for use for inducing pre-or post-operative sedation, anxiolysis, or amnesia, in patients suffering - or likely to suffer - from COVID 19 (SARS-COV-2 positive or exposed subjects), before medical chirurgical or invasive procedures occur. These medical invasive procedures usually occur in the Intensive Care Unit (ICU). Diazepam is therefore administered to these subjects before being transported to ICU, or in the ICU.
  • ICU Intensive Care Unit
  • Diazepam will prevent the worsening of the viral infection and will provide acceptable conditions for the invasive chirurgical procedure to take place (by placing the subject in an artificial sleep).
  • SARS-COV-2 positive or exposed subjects may have been previously treated with a BZRA or not.
  • these subjects are not currently treated with another BZRA of any kind.
  • Diazepam as a sedative agent in patients that have to undergo a harmful or invasive medical procedure (e.g., operation or endoscopy), when said patients suffer from a viral or bacterial infection being due to a Rhinovirus, the Ebola virus, the measles virus or the Japanese encephalitis virus or to the bacteria Pseudomonas aeruginosa, Staphylococcus aureus or Neisseriae gonorrhoeae. All the above detailed embodiments can also be applied to any of these viral or bacterial - infected subjects, to prevent strong / severe forms of the infections and subsequent lethality to occur.
  • a harmful or invasive medical procedure e.g., operation or endoscopy
  • the present invention therefore also proposes an in vitro method for evaluating the risk of suffering from a severe COVID 19 disease, once infected with the SARS-COV-2 virus. This method is based on the information whether the patient is currently treated with a BZRA, and, if so, if said BZRA is Diazepam.
  • SARS-COV-2 positive subject is treated with a BZRA which is not Diazepam, then the prognosis of said subject is poor. Said subject is indeed more likely to suffer from a severe or critical form of COVID 19 than subjects that are not treated with a BZRA or subjects that are treated with Diazepam. Also, his / her vital prognosis is more engaged.
  • the present invention gives a way to select patients that are likely to benefit from a BZRA treatment versus those who need to stop a BZRA treatment in order to avoid the worsening of the SARS-COV-2 infection.
  • said BZRA treatment should be taped off, and eventually stopped and Diazepam should be potentially administered instead.
  • the present inventors propose prognostic methods to assess the risk of mortality for patients suffering from a viral or bacterial infection being due to a Rhinovirus, the Ebola virus, the measles virus or the Japanese encephalitis virus or to the bacteria Pseudomonas aeruginosa, Staphylococcus aureus or Neisseriae gonorrhoeae. All the above detailed embodiments can also be applied to any of these viral or bacterial - infected subjects, if they are currently treated with a BZRA
  • the agent of the invention (the BZRA compound, should it be Diazepam or another BZRA) is preferably contained in a pharmaceutical composition.
  • This pharmaceutical composition herein also called the “pharmaceutical composition of the invention”, therefore comprises the BZRA agent of the invention and a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” or “excipient” refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the active principle alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts
  • dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions of the invention can contain any pharmaceutically acceptable salt of the agent of the invention (the BZRA compound, should it be Diazepam or another BZRA), or any functional derivatives, analogs, isomers, metabolites, solvate, clathrate, polymorphs or co-crystal thereof.
  • pharmaceutically acceptable salt is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
  • the pharmaceutically acceptable salts comprise:
  • the shaded areas represent pointwise 95% confidence intervals.
  • a multicenter observational retrospective cohort study was conducted at AP-HP, which includes 39 hospitals. All adults were included, aged 18 years or over, who have been admitted to these medical centers from the beginning of the epidemic in France, i.e. January 24 th , until May 1 st 2020. COVID-19 was ascertained by a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) test from analysis of nasopharyngeal or oropharyngeal swab specimens.
  • RT-PCR reverse-transcriptase-polymerase-chain-reaction
  • the data were from the AP-HP Health Data Warehouse ('Entrep Camill de Don Pains de Santé (EDS)'). This warehouse contains all available clinical data on all inpatient visits for COVID-19 to any Greater Paris University hospital. The data included patient demographic characteristics, vital signs, laboratory test and RT-PCR test results, medication administration data, medication lists during current and past hospitalizations in AP-HP hospitals, current diagnoses, discharge disposition, and death certificates.
  • EDS AP-HP Health Data Warehouse
  • Study baseline was defined as the date of hospital admission.
  • BZRA use was defined as receiving these medications at baseline, i.e., within the first 48 hours of hospital admission, and before the end of the index hospitalization or death, to minimize potential confounding effects of late prescription of BZRAs, which can be used in palliative care. This delay was used because it was considered that, in a context of overwhelmed hospital units during the COVID-19 peak incidence, all patients may not have received or been prescribed their usual medication regimens the first day of their hospital admission, or this treatment may not have been recorded at this time.
  • the primary endpoint was the time from study baseline to death. Patients without an end-point event had their data censored on May 1 st , 2020.
  • sensitivity analyses were conducted. First, a multivariable Cox regression model was performed, including as covariates the same variables as in the IPW analysis. Second, a univariate Cox regression model was used in a matched analytic sample using a 1:1 ratio, based on the same variables used for the IPW analysis and the multivariable Cox regression analysis. To reduce the effects of confounding, optimal matching was used in order to obtain the smallest average absolute distance across all clinical characteristics between exposed patients and non-exposed matched controls. 36 Third, to examine a potential indication bias of prescription of BZRAs in ICUs as a possible treatment for palliative care or as an aid to oral intubation, the main analyses were reproduced after excluding all patients who had been hospitalized in ICUs.
  • BZRA benzodiazepine receptor agonist
  • BZRA use was significantly associated with increased mortality among patients hospitalized for COVID-19. This association might be explained by several mechanisms. First, although the risk of respiratory depression associated with benzodiazepines in the general population is debated and was not found to play a substantial role in our study, it might be relevant among elderly patients with COVID-19 and in those with pre-existing comorbidities, such as chronic obstructive pulmonary disease. 41 Second, benzodiazepines might be associated with an increased risk of secondary infections, particularly pneumonia, in patients with COVID-19.

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EP21305168.3A 2021-02-08 2021-02-08 Utilisation de diazépam en tant qu'agoniste du récepteur de benzodiazépine seulement toléré chez des patients atteints de la covid-19 Withdrawn EP4039258A1 (fr)

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